Implantable device and method for the electrical treatment of cancer

ABSTRACT

An implantable electrical method and apparatus for the treatment of cancer tumors based on the usage of various levels of electrical fields and current to assist in specific ways to reduce tumor size. The appropriate voltage, currents, and time duration as well as the usage of adjunctive pharmacological therapy are taught.

[0001] This application is a continuation-in-part of U.S Ser. No.09/524,405 “Implantable Device and Method For The Electrical TreatmentOf Cancer” filed on Mar. 13, 2000 which was related to the provisionalapplication filed on Apr. 9, 1999, U.S. Ser. No. 60/128,505, entitled“Implantable System for the Electrical Treatment of Cancer.” Thisapplication is also based on provisional applications U.S. Ser. No.60/238,612 filed Oct. 10, 2000 entitled “Electrophoretic Drug InfusionDevice,” U.S. Ser. No. 60/238,609 filed Oct. 10, 2000 entitled“Implantable Therapeutic Device,” and U.S. Ser. No. 60/255,184 filedDec. 12, 2000 entitled “Method For Eliminating Possible Corrosion ofElectrodes in Electrochemical Therapy and Electrochemotherapy.”

BACKGROUND OF THE INVENTION

[0002] Cancer is one of the major causes of hospitalization and deathworldwide. Many of the therapies applied to cancer treatment are eitherineffective or not well-tolerated by the patient. A promising approachthat is little known but which has been successfully applied in Sweden,China, Germany, and Japan involves the electrical stimulation of amalignant tumor using direct current electricity. This has become knownas electrochemical treatment (ECT). The clinical results have beenobtained by applying electrical current via electrodes insertedpercutaneously into the tumor. The treatment lasts for several hoursduring one or more sessions and can be used either alone or inconjunction with other therapy such as chemotherapy or radiationtherapy. The therapy is well-tolerated in almost all patients.

[0003] This method is not to be confused with the electroporationtechnique which uses high voltages (˜1 kV) with very short pulses.

[0004] The present invention overcomes some of the disadvantages of theECT method mentioned above. It involves an implantable device consistingof a generator and one or more wires containing one or more electrodes.The electrodes are implanted in or near the tumor and the generator isimplanted subcutaneously as close to the tumor as practical. Thegenerator is powered either by an internal battery or via energy coupledto it from a source external to the body. The implantation is typicallyperformed under local anesthesia and the device is left implanted for aperiod of months. Implantation permits electric current to be applied atlower levels for longertime periods, thus overcoming some of thedrawbacks of the method above.

[0005] The nature of the implant results in some key differences fromcardiac pacemaker design allowing for less stringent requirements onpackage and wire longevity. Other differences are manifested in theanchoring of the electrodes and in functions of the generator. Thedevice complexity can range from very basic to sophisticated, includingprogrammability of multiple parameters, patient alert mechanisms,sensors, and telemetry of information. The system may also include anexternal instrument for programming, telemetry reception, and dataanalysis. In one embodiment, chemotherapy drugs are infused from thegenerator in addition to the electrical stimulation.

[0006] Disease Prevalence

[0007] Cancer malignancies result in approximately 6,000,000 deathsworldwide each year. Of these, 538,000 were in the United States in1995, representing over 23% of the total deaths in the United States.This number is up from 1970, when 331,000 deaths occurred. The estimatednumber of new cases in the United States in 1997 was 1,382,000. 40% ofAmericans will eventually be stricken with the disease and more than 1in 5 will die from it. The percentage is increasing at about 1% per yearand cancer deaths will soon outstrip deaths from heart disease. Much ofthe medical care cost from cancer results from hospitalization. In 1994there were 1,226,000 hospital discharges in the United States related tocancer treatment.

[0008] The cost of cancer in terms of both human suffering andexpenditures is staggering. Effective treatment methods which alsoresult in fewer days of hospital care are desperately needed.

[0009] Cancer Treatment Methods

[0010] Primary treatment methods used in cancer therapy include surgery,radiation therapy, chemotherapy, hormone therapy and many othersincluding bone marrow replacement, biological response modifiers, genetherapy, and diet. Therapy often consists of combinations of treatmentmethods. It is well known that these methods may result in sickness,pain, disfigurement, depression, spread of the cancer, andineffectiveness. Despite recent announcements of potentialpharmaceutical “cures,” these may work well in animals and in humans incertain cases, but researchers are cautious in overstating theireffectiveness.

[0011] The therapy made possible by the novel devices described in thisreport is seen to have many benefits, including:

[0012] They may be used for either the primary treatment of neoplasms orduring regression.

[0013] They require a single implant procedure, not repeatedapplications of invasive therapy, an important consideration inseriously ill individuals.

[0014] This and the lack of leads passing through the skin reduce thechance of infection.

[0015] Slow application of lower levels of current is preferable tolarger quantities of charge over a short period of time. Extended usemay prevent future metastases.

[0016] They have no disabling side effects as are found withchemotherapy or radiation therapy.

[0017] Their use is suitable in conjunction with other therapies.

[0018] Minimal hospital stays are required.

[0019] The device cost and complexity are low relative to pacemakers.

[0020] Since the therapy delivered by these implantable devices is basedon the theory and clinical experience of B. E. Nordenstrom and others,their work and conclusions are first summarized below.

[0021] Early and Related Studies of Electrical Current in Tumors

[0022] Reis and Henninger caused regression of Jensen sarcomas in ratsin 1951 using direct current and applied the technique to one patientwith vulvar cancer. Lung tumors were first treated with direct currentby Nordenstrom as reported in a 1978 publication. Experiments usingsmall amounts of direct current to inhibit tumor growth were performedby Schanble et al. as well as others. Srinivasan et al. mention thepossibility of controlling malignant tumor growth by direct current.Direct current has been used to coagulate blood in vessels leading totumors and others (circa 1980) experimented with electrolyticdestruction of tissue in animals using direct current (See Nordenstrom1983). Mir et al. successfully treated tumors with Bleomycin and eightpulses of 100 microsecond width at 1 Hz with a field intensity of 1500V/cm. They concluded that the minimum intensity required was 1100-1200V/cm.

[0023] The Work of B. E. Nordenstrom

[0024] Bjorn Nordenstrom of Sweden, a pioneer and inventor inpercutaneous needle biopsy and former Chairman of the Nobel Assembly,performed extensive research in electromedicine, developed a theory onthe nature of bioelectricity and the healing process, and treated cancerin his patients as clinical proof of his theories. He called his modelof biological control systems “biologically closed electric circuits”(BCEC) and sought to explain structural development in tissue injury andparticularly around cancers. He found that treatment of cancer with DCelectrodes changes the microenvironment of the cancer cells byelectrophoresis of water and fat and electro-osmosis of water. Thetherapy that is based upon this principle is called “electrochemicaltreatment” (ECT). Direct current ionizes tissue (as does ionizingradiation). Ionization of tissue via direct electrodes affects normaland malignant tissues differently. Low energy levels build up thetherapeutic dose of energy from the inside of the tumor.

[0025] Tumor cells are more sensitive to changes in theirmicroenvironment than are normal cells. The effect of the application ofdirect current to cells with platinum electrodes has been summarizedsuccinctly by Li et al.:

[0026] Water migrates from the anode to the cathode while fat moves inthe opposite direction (this migration causes local hydration around thecathode and dehydration around the anode).

[0027] The tissue becomes strongly acidic at the anode and stronglyalkaline at the cathode.

[0028] The distributions of macro- and microelements in the tumor tissueare changed.

[0029] Protein is denatured in the electrochemical process (hemoglobinis transformed into acid hemming around the anode and alkaline hemmingaround the cathode).

[0030] Chlorine, which is a strong oxidant, is liberated at the anode,whereas hydrogen, which produced local cavitation in the tissue, isliberated at the cathode.

[0031] By means of DC delivering adequate electric charge, a series ofbiological and electrochemical reactions take place in tissue. The cellmetabolism and its existing environment are severely disturbed. Bothnormal and tumor cells are destroyed rapidly and completely in thisaltered environment.

[0032] Berendson et al. believe that the toxic properties of thechlorine close to the anode and of the hydrogen chloride within abroader zone may be enough to explain the clinical effects of ECT andthat the liberated hydrogen ions determine the extension of the locallydestroyed zone around the anode. Several researchers have also observedthat destruction occurs around both anode and cathode (Song et al.,Matsushima et al., and Xin et al.) as well as within the electric fieldestablished between them. (In early works Nordenstrom cautions againstmaking the center of the tumor the cathode as it will causeconcentration of the acidity at the wrong location but later reportsthat, in some cases, better results were achieved with the cathode atthe tumor.) Subsequent work in Asia found an advantage in locating bothelectrodes within the tumor (Xin, 1997). Nordenstrom believed that theelectro-osmotic transport of water compresses capillaries and was seento block large pulmonary arteries in dog experiments. He points out thata sufficiently long interval of vascular obstruction will seriouslyinterfere with the living conditions of the tissues. Thus, primary tumordestruction is obtained, along with a change in surrounding conditionsthat prevent the tumor from living. ECT is also believed to enhance theimmune system of the patient (Chen et al., Chou et al). In studiesconducted in mice there was infiltration of lymphocytes in tumor tissuesix days after treatment. Leukocytes have a negative surface charge andare known to be sensitive to low voltage changes and changes in pH andion strength. At an electrode voltage as low as 100 mV leukocytesconcentrated at the anode. Many leukocytes can be attracted to the anodeat relatively low voltages but are massively destroyed in the anodicfield at 10 V. Nordenstrom recognized that electrophoretic movementswill take place at low voltages and current densities and he discussedpossible tissue changes with, for example, 10V and 1 to 2 microamperesapplied for 30 days. He wrote “. . . it seems likely that DC treatmentshould be most beneficial when the technique approaches the mechanismsof closed circuit transport in spontaneous healing. This considerationimplies the use of energies perhaps in the range of a few volts and afew microamperes over long time periods.” He also deduced that ACpotential may be used to heal tissue.

[0033] Procedurally, Nordenstrom used electrodes such as those shown inFIG. 1. The electrode is introduced through the chest wall (in the caseof lung tumors) into the patient under guidance of biplane fluoroscopyor computed tomography under local anesthesia. In FIG. 1a hookedelectrode ends 1 of platinum strings protruding from plastic tube 2expand within tumor 3 to retain the electrode inside the tumor. In FIG.1b platinum tubes 10-12 provide a larger surface area and can be chosento correspond with the size of the tumor. Screw 14 is used to obtainbiopsy tissue samples. The electrode 13 is shown implanted in tumor 20in FIG. 1c. Tube 21 is constructed of Teflon®. Alternatively, FIG. 1dshows a tapered platinum tube 30. Screw 31 is used to obtain tissue forbiopsy. Area 32 consists of collapsed wings which, as shown in FIG. 1e,expand 40 to stabilize electrode 30 in the tumor. Nordenstrom recognizedthat a platinum electrode can be improved mechanically by addingiridium. He stated some guidelines for electrode design andimplantation. The electrodes should present a large surface area butmust be easily introducible without causing too much damage. Herecognized in 1994 that regression of cancer can take place both aroundthe anode and the cathode in the tumor. Placement of both electrodeswithin the tumor can lead to a treatment result comparable with aninitially successful surgical removal of a cancer. However, as withsurgical removal, metastases may later start growing in the tissuearound the former tumor site. Positioning the anode and cathode farenough away from each other will create a distant field effect thatshould prevent future metastases. Thus, he believed that ECT of “smallresectable” cancers might be more efficient than conventional surgicalresection. He advised that the use of multiple anodes and cathodes mightcause an uneven distribution of current and recommended that electrodesbe neither very close nor very far away from one another. The anodeshould be kept away from direct contact with large blood vessels ifusing the large currents and voltages used by Nordenstrom (but not withmicroampere level currents). The cathode may be placed in a bloodvessel. Nordenstrom used a catheter that could be percutaneouslyinserted by Seldinger technique in, for example, a pulmonary artery.Electrodes can theoretically be placed on the skin (although he cautionsagainst this in a later paper) or inserted through a chest wall, via asystemic artery, a systemic vein, a bronchus or in the pleural space.The venous routes and pleural space provide pathways for current thatinclude the lymphatics. Nordenstrom also noted that flushing the anodalelectrode with a charged agent such as Adriamycin or 5-fluoracil in amanner that causes even distribution of the drug with high concentrationcan lead to a remarkable regression and palliative effects of evenlarge, incurable cancers. Whether supplied intravenously or orally,these two agents are attracted to the electrode, when given oppositepolarity.

[0034] Nordenstrom reported treatment of 26 inoperable cancers of thelung in 20 patients starting in 1978 and followed up for 2 to 5 years.Twelve of the cancers were arrested and no fatalities occurred. Heobserved that in some cases multiple other small metastases in the lungparenchyma, distant from the sites of the electrodes, also appeared toregress after treatment of the larger metastases. He pointed out thatthe therapy was unoptimized at that time. Radiation treatment of lungtumors is not very effective. A rapid decrease in size of a poorlydifferentiated tumor after radiation treatment is often accompanied byre-growth of the tumor after a short time. Then the tumor is often moreinsensitive than previously to any attempts at a repeat course ofradiation treatment. He foresaw an advantage of DC current treatment ofprimary neoplasms in the most surgically inaccessible locations such asthe brain, spine, pancreas, liver and prostate and in patients who havebeen rejected for surgery, radiotherapy or chemotherapy because of poorgeneral condition, cardiorespiratory insufficiency, diabetes mellitus,multiple locations of pulmonary metastases or failing response tochemotherapy. In a later report he cited favorable results with breastand bladder cancer. Also, he treated 14 patients with otherwiseincurable cancers with ECT and a chemotherapeutic agent Adriamycininfused into the tumor. The principle, already mentioned above, is thatan intramuscularly electropositive compound will be electrophoreticallyattracted to a neoplasm electrode given opposite polarity. Thistreatment was successful on largertumors than was ECT alone and, in onecase, abolished chronic cancer pain. Electrophoresis caused evendistribution of the Adriamycin throughout the tumor, an effect probablynot obtainable with injection.

[0035] Recent Human Results in Asia

[0036] B. E. Nordenstrom introduced electrochemical therapy in China in1987 and, partly because of its relationship to traditional Chinesemedicine (e. g., acupuncture), its use has been growing in China andinterest has spread to Japan and Germany. Xin reported that, by 1994,4081 malignant tumor cases were treated using ECT in 818 Chinesehospitals including esophageal, breast, skin, thyroid and liver cancers,as well as leg sarcomas. By the end of 1994 more than 6000 cases hadbeen treated. Benign tumors such as heloid, angioma and freckle havealso been treated.

[0037] Xin et al. published the results of treatment of 386 patientswith lung cancer between 1987 and 1989. They found that damage of normaltissue could be eliminated by placing both electrodes into the tumorwith anodes in the center and cathodes on the periphery. This has alsoenhanced the therapeutic effect significantly. They also concluded thatthe effect of ECT with lower current and longer treatment time is betterthan high current and shorter time.

[0038] Matsushima et al. and Chou et al also placed both electrodesinside the tumor. Matsushima et al studied 26 patients with 27 malignanttumors. The main complications were pain and fever for a few days aftertreatment. Pain during treatment, especially when the lesion was locatedin the neck or in soft tissue under the skin, was probably due tosensory nerve stimulation by the direct current. Some lung cancerpatients had haemoptysis and pneumothorax.

[0039] Song et al. reported the treatment of tumors on the body surfacewith good results. ECT was found to be suitable for patients at greatoperative risk, for those who refuse surgery, for those who have notbeen cured by other means, and for those who have tumor recurrence. Theydiscovered that metastatic enlarged lymph nodes can dissolve when theprimary tumor is destroyed by ECT. The method was found to be simple,safe, effective, and readily accepted by patients. ECT can be used inprimary as well as metastatic tumors, although the effect is better forprimary tumors.

[0040] Lao et al. reported on the treatment of 50 cases of liver cancerusing ECT. The indications for treatment were: the neoplasm was toolarge to be easily resected; it was unresectable because of location atthe first or second hepatic portals; poor liver function secondary tosevere cirrhosis making the patient unfit to stand the trauma caused bysurgery; cancer infiltration of visceral organs such as thediaphragmatic muscle, peritoneum, or lymph nodes at the hepatic portals.

[0041] Quan discussed the ECT treatment of 144 cases of soft tissue andsuperficial malignant tumors. Short-term effectiveness of treatment was94.5% for tumors with a diameter of less than 7 cm. and 29.4% for tumorswith a diameter of more than 7 cm. He found that the earlier the stagethe more effective the treatment and that ECT for malignant melanoma ismore effective than chemotherapy and no different in results fromsurgery. However, ECT eliminated the need for amputation and dysfunctionoften caused by a too wide surgical excision.

[0042] Wang reported on ECT for 74 cases of liver cancer with tumorsranging from 3 to 20 cm. in diameter. The treatments of 3 to 5 hourswere repeated 2 to 5 times with 7 to 10 days between each treatment.Total remission rate was 63.51%. Best results were obtained with tumordiameters less than 9 cm. Additional use of cytotoxic drugs andembolization resulted in a 87.5% cure rate.

[0043] Song et al. treated 46 patients having thyroid adenoma with ECTand reported a 97.8% cure rate with a single treatment. This representssuccessful treatment of benign tumors and destruction of precancerousand early malignant changes.

[0044] The above reports from China vary in the amount of technicaldetail presented regarding each study. In general, however, theelectrodes were inserted under local anesthetic. The number ofelectrodes depended upon the tumor size and shape. The goal was toencompass the tumor with the electric field. Xin et al. state that,depending upon tumor composition and location, soft, flexible or hardelectrodes with 0.1 cm diameters were used. The anode(s) was(were)placed within the tumor and the cathode(s) was(were) separated by from1-3 cm. from the anode(s) or by a distance of 2-3 tumor diameters. Therewere a minimum of 2 electrodes and, at the other extreme, 2 anodes and4-6 cathodes set up in two groups to establish two electric fields for atumor of 6 cm. or larger. The treatment time varied from 1.5-5 hours andthe number of sessions ranged from 1 to 5, again depending upon tumorsize and response to therapy. The voltage used averaged about 8V butranged from 6 to 15 V. The current ranged from 40-100 mA and the numberof coulombs delivered per session ranged from 250 to 2000° C. Quan givesa rule of thumb at 100° C. per 1 cm of tumor diameter. Song observedthat, at 100° C., the area of destruction around the anode is 0.5-0.6 cmand the area around the cathode is 0.4-0.5 cm. Xin et al. observed someblockage of the heart beat in central lung cancer ECT with currents over30 mA. Keeping the electrodes more than 3 cm from the heart correctedthis effect.

[0045] The table below summarizes the types of tumors mentioned ashaving been treated by the researchers cited above: Author Tumor orCancer Type Xin et al. Lung, squamous cell, esophageal, parotid, breast,sarcoma of the leg, skin, malignant melanoma, cartilage sarcoma of nose,thyroid, liver, keloid, angioma, freckle Matsushima Skin, breast, lung,gland et al. Song et al. Skin, malignant melanoma, lip, tongue, upperjaw parotid, breast, vagina, penis, osteogenic sarcoma, fibrosarcomametastatic lymph node Lao et al. Liver (hepatocellular carcinoma,cholangiocellular carcinoma, mixed hepatocholangiocellular cancer,transparent liver cancer) Quan Soft tissue sarcoma, head/neck cancer,malignant melanoma, skin cancer, breast cancer, recurrent cancer,metastatic cancer Wang Liver

[0046] Animal Results

[0047] Yokoyama et al. used direct current in canine malignant cancertissue and found that cancer tissues of 2 cm. in diameter around theelectrode became necrotic in 60 minutes. Bleomycin was then injectedintravenously and was found to accumulate around the electrode in themajority of cases. Li et al. studied the mechanisms of ECT in normal dogliver and verified that the cell metabolism and its environment aredestroyed in agreement with previous theory. Chen et al. studied ECT inmice and verified much of the theory, including the conclusions thattumor cells are more sensitive to changes of their microenvironment thanare normal cells and that ECT stimulates the immune system, pointing outthat, at an electrode voltage as low as 100 mV, leukocytes concentrateat the anode and lymphocyte anti-tumor response might be activated. Liet al., like Xin, placed both an anode and a cathode in the tumor. Chouet al. investigated ECT in mice and rats. Pointing out that constantvoltage is used in clinics to prevent pain, they used a constant-voltagemode. They also cite the observations of Xin that untreated tumorssometimes disappear after ECT of the primary tumor. The hypothesisproposed to explain this was that the immune system was enhanced by ECT.

[0048] Electroporation

[0049] Another electrical therapy that has been attempted for thetreatment of cancer is electroporation. This is based on the effectivehigh voltage shocks which temporarily open pores in the cell membranes.This is normally considered a negative byproduct of shocks and is anegative side effect of, for example, defibrillation therapy. Theapplication of a high voltage shock with fields on the order of hundredsof volts per centimeter will raise the transmembrane potential of thecell above 500 mV. This is over five times the normal activationpotential swing of a cell and causes micro-pores to be temporarily open.If opened too long the pores are permanently damaged. The effect of thiselectroporation is a dramatic increase in the molecular exchange betweenthe inside and outside of the cell.

[0050] Electroporation has primarily been used as a research tool andbeen evaluated for assistance in injecting various drugs, geneticmaterial, proteins, and other substances into cells. Okino et al. usedelectroporation therapy and a cancer drug in an animal study.

[0051] Orlowski et al. also published another use of electroporation (hereferred to it as electropermeabilization) of culture cells to increasethe effectiveness of anti-cancer drugs. Belehradek et al. and Hofmann etal have both reported on the use of electroporation specifically toincrease the efficacy of Bleomycin respectively in animals and humans.

[0052] There have been several patents discussing electrical treatmentfor cancer. These are primarily due to Nordenstrom as discussed here.All of these systems have been external instruments and there is nodiscussion or hint that the inventors here are aware of or conceived ofa fully implantable or even a battery operated system.

[0053] Nordenstrom et al. patented an instrument for destroying aneoplasm in 1981. An instrument external to the body provides directcurrent and integrates it to determine charge. Electrodes are placed inthe body, one in the neoplasm and one a distance away from it. Theinstrument controls the maximum voltage and current and can interruptthe current when the calculated charge reaches a predetermined value. Inanother patent granted to Nordenstrom in 1990 his concern was with aphysiological way of healing, growing, or modifying tissue by applying atime-varying voltage. The voltage is a damped sine wave or a similarshape, each half cycle of the sine wave adjustably ranging from 0.1 to10 days. The system can sense the direction of physiological healing andadjust the polarity of the voltage phase to complement it. In practicethis is a system that appears to be used long-term but is not describedas implantable except for the electrodes. The patent mentions thepossibility of a rechargeable power source, programming of thecontroller, and automatic shutoff. D. Fontaine et al. patented a devicereminiscent of an ablation device in 1996. It is of interest in that itincludes a catheter tube containing electrodes as well as a lumen forthe flow of electrolyte fluid to match the impedance of the tissue tothe energy source. This is one example of catheters having electrodes aswell as the ability to deliver fluids. B. Nordenstrom et al. patentedanother in 1986 for treatment of tumors. The patent discusses itsadvantages in positioning and retention of the electrode, in overcomingproblems of gas formation and dehydration at the tumor, and the problemof material deposition on the electrode surface. The control instrumentis specified as outside the body. Examples of fluids that can bedelivered are cited as sodium chloride solution to increase theconductivity of the tumor as well as cell poison. Another patent toNordenstrom in 1990 concerns a temporary electrode device suitable forthe tumor destruction application. It was designed for ease of entry andremoval and has an adjustable length electrode to adapt to differentsize tumors. P. Eggers et al. received a patent in 1997 for aninstrument and a probe with two electrodes to sense whether tissue isnormal or tumorous and, in the latter case, benign or malignant. Methodscited include measurement of impedance or dielectric constant. It alsoincludes treatment of the tissue mass to effect necrosis, preferably viaheat to cause cauterization. The device is specifically intended for useover a brief period of time.

[0054] There have been several patents dealing with the use ofelectroporation to inject substances into cells. For example Calvinteaches the use of electroporation to introduce DNA while Hofmannteaches several variations on this theme.

[0055] All of the patented art deals with either fully or largelyexternal systems. This ranges from patches around the neck to externalpower sources into temporarily introduced needles and catheters. Theseall require use of a catheterization laboratory with all of theattendant costs and personnel, or could be conceivably used with a riskof infection with leads being left in the body and crossing the skinbarrier.

[0056] With the possible exception of the painful high voltage shocks ofelectroporation therapy, it appears that the optimal electrocancertherapy obtains from long-term application of low voltages. This wouldseem to suggest that a battery operated implantable device would beoptimal. However, this had not been taught in the literature. Theclosest are some semi-implantable systems such as an implantable RFHeater of Doss which has a coil inside the body which picks up a veryhigh powered magnetic transmission and converts the heat. Similarly,Hofinann (U.S. Pat. No. 5,501,662) teaches a partially implanted systemin which electrodes are left in a blood vessel to shock blood cells,receiving its power from an induction coil again from a high poweredoutside source. Neither of these is suitable for chronic care.

[0057] Thus, in spite of the evidence beginning to accumulatedemonstrating the usefulness of some types of cancer electrical therapy,there has been no teaching by a practical implantable device. Such adevice could cost effectively and safely deliver cancer therapy withoutthe risk of infection from repeated introduction of needles andcatheters into the body.

[0058] Also, the use of a system that would use all levels of electricaltherapy for cancer treatment has not been taught even on an externalbasis.

BRIEF DESCRIPTION OF THE DRAWINGS

[0059]FIG. 1 shows leads that have been used in acute research studies.

[0060]FIG. 2 shows the overall system of the invention.

[0061]FIG. 3 shows the lead placements of the invention.

[0062]FIG. 4 shows the lead systems of the invention.

[0063]FIG. 5 shows the basic generator of the invention.

[0064]FIG. 6 is a graph of current vs. time for treatment of a pulmonarytumor.

[0065]FIG. 7 shows the advanced generator of the invention.

[0066]FIG. 8 shows the method of the invention.

[0067]FIG. 9 shows the voltage profiles of the invention.

[0068]FIG. 10 shows the generator housing being used as an electrode.

[0069]FIG. 11 shows other electrical profiles useful in this invention.

[0070]FIG. 12 shows a tumor to which 5 electrodes have been applied inan array.

[0071] FIGS. 13-16 depict various electrode array embodiments of theinvention.

[0072]FIG. 17 depicts an array of electrodes in a tumor.

[0073] FIGS. 18-20 depict the port embodiment of the invention.

[0074] FIGS. 21-24 depict drug infusion embodiments of the invention.

[0075] FIGS. 25-28 depict catheter designs for the drug infusionembodiments.

[0076]FIG. 29 depicts an earlier drug pump device.

[0077] FIGS. 30-32 depict a drug and electrical catheter of thisinvention.

[0078] FIGS. 33-36 depict methods for dealing with electrode corrosion.

DETAILED DESCRIPTION OF THE DRAWINGS AND PREFERRED EMBODIMENT

[0079] The system for cancer therapy consists of a body implantedgenerator 51 and one or more implanted wires or leads 52 as shown inFIG. 2. The generator and leads are implanted in body 53, generator 51in a convenient subcutaneous area as near as practical to tumor 54 butout of the path of any planned ionizing radiation and leads 55 and 56are implanted in or outside tumor 54. Anode electrode 55 is typicallyimplanted in the center of tumor 54 and cathode electrode 56 istypically located either outside tumor 54 or on its internal periphery.Leads are tunneled subcutaneously from generator 51 to tumor 54. Thelead containing electrode 56 can alternatively be introduced into ablood vessel and be placed in a location near the tumor 54. The systemalso consists of an instrument 57 used to communicate with thegenerator.

[0080] The system has both similarities and differences from implantablepacemaker systems. Among the differences are:

[0081] Duration of implant is typically months, not years.

[0082] The system is non life-supporting.

[0083] The generator, by virtue of its expected longevity, has lowerhermeticity requirements.

[0084] The leads have less stringent mechanical requirements since theyare not stressed by movement to as great a degree and since they have ashorter required longevity.

[0085] Lack of concern for electromagnetic interference.

[0086] Other differences and unique features will be discussed below. Itshould be mentioned that the complexity of the device can varyconsiderably, depending upon its desired flexibility of use. In thesimplest case it can consist of a single lead permanently connected to agenerator encapsulated in a plastic or potting compound with a fixed DCoutput voltage and no external instrument for communication and control.However, this discussion will range over the entire scope of optionspossible for this system.

[0087] 1. Leads

[0088]FIG. 3 shows options for the lead system. In FIG. 3a a unipolarlead 60 has one electrode 61 implanted in or adjacent a tumor 62. Thegenerator 63 serves as the reference electrode. In FIG. 3b multipolarlead 70 has 2 or more electrodes 71, 72 implanted in or adjacent a tumor73. Electrode 71 would serve as the anode and 72 would serve as cathodeor vice versa. In FIG. 3c lead 80 has one or more electrodes 81implanted adjacent tumor 82 and lead 83 has one or more electrodes 84implanted adjacent tumor 82. A variation of FIG. 3c is represented byFIG. 2 in which the anode electrode 55 is implanted within tumor 54.Many variations are possible. The goal is to establish an electric fieldencompassing as much of the tumor as possible and as little of thesurrounding area as possible. FIG. 3d shows three leads 90-92.Electrodes 93 and 94 are anodes and electrodes 95-98 are cathodes.Alternatively, two separate circuits can be established with electrodes93, 95 and 97 forming one and electrodes 94, 96, and 98 forming theother. The leads may be permanently connected to the generator or may beattached with a releasable mechanism, depending upon the desired costvs. system flexibility. For example, the low cost system would employleads of fixed length and means of anchoring to the tissue. Those leadswould not be removable from the generator. Lead and electrode materialmay be of the kind used in implantable pacemakers, i. e., inert metalssuch as platinum but generally without the need for sophisticatednon-polarizable electrodes. The major stress will be placed upon theleads during implantation and their strength should be a compromisebetween reducing the diameter and being able to withstand kinking duringimplant. A few strands of platinum iridium coated with insulation shouldsuffice per electrode. A lumen or stylet aperture is optional.

[0089] Leads may be supplied in various lengths or in a single length,with excess lead being wrapped around the generator in its body“pocket.” The system may provide lead adaptors to permit the use ofadditional leads for largertumors as illustrated in FIG. 3e in whichlead adapter 100 allows leads 101 and 102 to enter generator 103electrically at the same location 104. The most complex and costly leaddesigns contain sensors (as described below).

[0090] The lead anchoring mechanism represents an importantconsideration. It is generally anchored in tissue quite different fromheart muscle, typically softer. The anchoring mechanism must permitpenetration of the tissue, anchoring in soft and retracting tissue, andsafe removal. FIG. 4 shows several possibilities. FIG. 4a shows ascrew-in lead 150 having a screw 151 designed to be left within thetumor 152 during therapy. In FIG. 4b lead 160 features 2 or more prongs161 which expand into tumor 162 and are left expanded during therapy.The anchoring for the leads of these devices is more akin to so-calledactive fixation pacing leads than to passive fixation leads. Themechanisms in FIG. 4 may or may not be used as electrodes as well asanchoring means. Ideally, lead design would be specific to the type,size and location of the tumor. FIG. 4c shows a lead 170 having two ormore overlapping telescoping cylindrical electrode sections 171, 172which may be adjusted either pre- or post-implantation to an optimumlength. In the figure electrode section 171 has been extended fromelectrode section 172.

[0091] 2. Generator

[0092]FIG. 5 shows a block diagram of the most fundamental generator200. The power source 201 may be a primary battery, a rechargeablebattery, or a receiver of RF energy coupled from outside the body. Inthe preferred embodiment battery voltage is available to driver circuit203 which provides DC current to the lead electrodes 204, 205.Controller 202 permits the voltage to be turned on or off by the patientor physician and may consist of a magnetic reed switch activated by anexternal permanent magnet. Driver circuit 203 delivers regulated voltageor constant current to the electrodes to compensate for changes inimpedance seen at the electrodes.

[0093]FIG. 6 is a graph of current in mA vs. time for treatment of apulmonary tumor taken from Nordenstrom. The voltage was 10 V and 250coulombs were delivered. In the implantable device, the same number ofcoulombs can be delivered at 50 microamperes if supplied for 100,000minutes, or 69.4 days. Alternatively, the generator can deliver 10microamperes at 10 V for 347 days. This represents a practical device.Perhaps a more attractive device would operate at 8 V and deliver 20microamperes for one year. This would deliver about 500 coulombs andwould, in the light of present clinical experience, be usable for mosttumors.

[0094] A typical Lithium Iodide cell has an output impedance on theorder of 1 KΩ and thus is limited to providing an averagecurrent ofunder 1 mA. The above current profiles could be easily provided.However, a carbon monofluoride cell has much lower output impedance andis more suitable for generating EPT shocks. The implantable device maycontain multiple power sources, each suitable for a different therapy.For example, one might use a rechargeable cell for higher currentapplications.

[0095]FIG. 7 shows an enhanced block diagram of generator 210 in whichseveral parameters can be programmed, including voltage or currentamplitude and output polarity (to switch anodes and cathodes). It mayalso allow programming the total number of coulombs to be delivered tothe electrodes. This is accomplished via transducer 211 and controller212 using commands transmitted by external instrument 213. Telemetrycircuit 214 allows information to be transmitted to the externalinstrument 213 from the generator 210. This includes battery status (e.g., remaining life), coulombs delivered, and information sensed from thetumor via the electrodes 215, 216 or via special sensors. The sensedinformation supplies tumor size, density, or chemistry data. Forexample, pH may be measured at the tumor. Other embodiments include ameasurement of pressure as the tumor shrinks or grows, an index of tumorproliferation, or an electrode displacement indication. These may beaccomplished via physical sensors such as measurement of electrode/tumorimpedance, pressure measurement, or optical sensing or by chemicalsensors. Note that chemical sensors are more practical for use in thisdevice than in implanted pacemakers because of the shorter duration ofthe implant and thus the lower sensor stability requirements.

[0096] The electrode device may contain a thermocouple or thermistor tosense heating of the tumor environment as a measure of safety and degreeof necrosis. Sensors will be designed to be exposed to ionizingradiation if radiation therapy is probable. Sensed information isprocessed at signal processor 217 and can be telemetered 214 to externalinstrument 213 via transducer 211 and/or can be used to control thegenerator directly. For example, sensing of excessive heating or gasbuildup can cause the therapy to be stopped until the tissue cools orthe gas is resorbed. Other features of the generator may includedefibrillation protection, a controller that gradually increases voltageat the start of the treatment, a programmable timer to control durationof therapy or sequence of therapy, and a warning signal 218 (e. g.,audible or vibration) to the patient to signal battery depletion, openor short circuit or other conditions warranting attention. The entiredevice is preferably under control of a microprocessor 219, although itssimplicity may not require computer control. Driver 220 may have severalsections, each suitable for a different therapy depending on the voltageand current levels required. Portions of the entire device may beoperated in a “sleep” mode to conserve energy when not in use.

[0097] Signal processor 217 is preferably a DC amplifier which woulddetect the intrinsic body “healing” currents being generated to run tothe tumor. The generator can begin the process by “priming the pump”with a short duration DC current which should help the body initiate itsown therapeutic currents. Output current levels may be either programmedor adjusted automatically to optimum levels to minimize tumor cellproliferation.

[0098] Although electrical stimulation alone has been shown to beeffective, it has most often been used in conjunction with chemotherapyor radiation therapy. Periodic chemotherapy may be applied bytraditional means independent of the implant. Alternatively, the implantmay be designed to supply the chemotherapy as well as the electricalstimulation. In a first embodiment of this concept the generatorcontains a subcutaneous port for penetration by a hypodermic needle. Thedrug is infused in real time through the port and through a deliverytube into the tumor. The delivery tube may be built into the lead or itmay be a separate tube. In the second embodiment, the generator containsa reservoir for storage of the drug. Under control of a timing circuitthe drug is released through a tube into the tumor. The technology ofimplantable drug infusion pumps, ports, and tubes is well known.

[0099] In the discussion that follows, the electrical therapy isdescribed as being the application of voltages. The therapy could justas well be described in terms of currents by application of the famousOhm's law which states that the voltage and current are proportional. Ofcourse, this proportionality constant is the resistance in theelectrode/tissue system. Because of changing resistances with long termDC electrical therapy, some physicians may choose to program the devicesin terms of current instead of voltage.

[0100] Thus, while the following discussion and claims are rendered interms of voltages, they should be considered to also refer to theappropriate currents.

[0101]FIG. 8 shows the basic method of the invention. First at step 240the anodal lead is implanted into the tumor. At step 242 the pulsegenerator is implanted at least several centimeters away from the tumor.If adjunctive chemotherapy is desired then the remote cathode is alsoimplanted at step 244 beyond the injection site or somewhat out of thedirect path from the tumor to the injection site. The remote cathodecould be left in a large vein. The pulse generator is programmed bytelemetry at step 246.

[0102] The following electrical parameters are all programmable by thephysician and thus should only be seen as illustrative. The firstelectrical therapy 248 is the supply of 10 volts between the anodalelectrode and the generator housing for a period of 1 hour. This willchange the pH in the tumor and begin rapid destruction. A voltagebetween 1 and 20 V is practical for this function. Durations between 10minutes and 1 day are useful for this application. A pH change down toabout 2 and up to about 13 are found respectively at the anode andcathode. A pH change of at least 2 will be required to begindestruction.

[0103] Then a low voltage field of 100 mV is applied at step 250 for 1day between the anodal electrode and the housing. This providesleukocytes (white cells) to the tumor to begin cleaning up the aftermathof the initial destruction. Note that these durations are not attainablewith pacemakers (which typically generate 1 mJ pulses). A 100 mV voltagefor one day with a system impedance of 1000 Ω requires nearly 1000 timesas much energy ( 864 mJ). This voltage should be high enough to attractthe white cells but below the electrolysis level as the high levels ofoxygen are not desired at this point. Voltages between 20 mV and 500 mVare appropriate. Durations in the range of 1 hour and 1 week are usefulfor this function.

[0104] At step 252 the chemotherapy bolus is injected. At step 254 thegenerator produces a field of 1 V for preferably 1 to 30 minutes(although the circuitry would allow up to 2 hours) between the anode andthe remote cathode to attract the chemotherapeutic agent to the tumor.The polarity at the tumor depends on the net charge of the dissolvedchemotherapy drug, e.g. for a negatively charged drug, the tumorelectrode polarity would be positive. The amplitude of this voltage canvary from 100 mV up to about 10 V although the 1 V range is preferredfor energy conservation reasons.

[0105] At step 256 the generator produces a large field of 200 V for 10ms pulses 100 times (with 10 ms spacing in between) between the anodeand the remote cathode to force open the cancer cell membranes(electroporation) to facilitate the entry of the large drug moleculesinto the cancer cells. The use of a smaller field from 20 V pulses wouldbe of utility but would not require as much energy usage and batterycapacity. Voltages up to 900 V would be even more beneficial and arepractical to generate in an implantable device. Pulse widths in therange of 100 μs to 20 ms are practical for this particular function.Spacing periods of 100 μs to 1 second are appropriate between thepulses. The repetition of 100 times is only illustrative and repetitionsof 1 to 10,000 pulses are useful for this electroporation function.Also, the device gives the physician the option of choosing the devicehousing as the remote electrode based on the considerations of patientcomfort, safety (avoiding cardiac fibrillation), and electroporationeffectiveness.

[0106] At step 258 the generator begins monitoring the voltage betweenthe anode and the pulse generator housing. If an intrinsic healingcurrent is detected then no further therapy is provided until the deviceis reprogrammed and the system sits in idle mode of step 260. If nohealing current is detected then the system will provide a field of 100mV between the anode and the generator housing in step 262 until turnedoff. Voltages between 20 mV and 500 mV are appropriate. Durations in therange of 1 hour and 1 month are useful for this healing currentfunction.

[0107]FIG. 9 shows the voltage profiles of the invention as describedunder the method above. Profile 300 is that between the anode and thehousing while profile 302 is that between the anode and the remotecathode.

[0108]FIG. 10 shows the body current paths. Note the primary therapeuticcurrent 340 is between the anode (in the tumor) and the pulse generatorhousing as the cathode. The secondary current 342 is between the anodeand the remote cathode. Preferably, the generator is located near thetumor and is the cathode for all currents except for the chemotherapyelectrophoresis. In that case, one desires to have a remote cathode faraway to better direct the intravenous drugs to the anode. This is thesecondary current 342.

[0109]FIG. 11 shows other possible variations in current levels for thistherapy. In FIG. 11a the therapeutic current level 362 is attained bygradually increasing the current 361 from the initial baseline 360. InFIG. 11b therapeutic current 370 is increased to level 371 in responseto an input from the microprocessor and later restored gradually 372 toits original value 73. These changes may be in response to a sensorinput, to circadian or other body rhythms, or to a change in measuredheart rate variability. FIG. 11c shows a therapeutic current level 380and multiple electroporation therapies 381 applied at desired times,perhaps corresponding to chemotherapy sessions.

[0110] The electroporation pulses may be biphasic and may be appliedsynchronously with a detected heartbeat in order to reduce the risk ofinducing cardiac arrhythmias. Feedback may also be used to adjustelectroporation parameters. For example, the electrical consequences ofelectroporation may be used to adjust the distribution of the electricalfield at the electrodes. FIG. 11d shows the use of electrochemicaltherapy with a healing signal 390 generated within the implantabledevice. After it has been determined that the tumor has been destroyed,at the time designated at 391, the device applies a healing current tothe former tumor site.

[0111] The implantable device may be used in conjunction with radiationand chemotherapy. By employing it over a long time period it helps killsome malignant cells that have developed resistance to radiation or toanticancer drugs. The implant can be used to aid in genetransfer therapyand electroimmunotherapy as well as in conjunction with vasoconstrictiondrugs. It can be used with hyperthermia, ultrasonics, and magnetotherpayas well.

[0112] As an alternative embodiment, the device can be programmed toawait a command from the patient to begin any stage of the electricaltherapy.

[0113] Electrode arrays can be particularly important in increasing theeffectiveness of electroporation therapy. They work to establish anelectric field pattern that encompasses all of the tumor volume. FIG. 12shows a tumor 400 to which 5 electrodes have been applied in an array.Four of the electrodes are shown in the figure. Electrode 401 is affixedto the top of the tumor and electrodes 402, 403, and 404 encircle thetumor. Electrode 401 is electrically connected to wire bundle 406 viainsulated wire 405. Each of the other four electrodes is individuallyconnected to bundle 406 in similar fashion. Wires 406 are attached tothe generator package. Each electrode is fixed to tissue via a needlesuch as 407 which may or may not be part of the electrode. This arraycan be used for both electrochemotherapy or electroporation.

[0114] Current paths can be switched by the implantable generator sothat, for example, a current pulse can flow from 404 to 401, then from403 to 401, then from 402 to 401, etc. in any desired sequence. Two ormore electrodes may simultaneously be used as anodes or cathodes for DCtherapy.

[0115] An array similar to that of FIG. 12 is shown schematically inFIGS. 14b and 14 c. FIG. 14b is a top view and FIG. 14c is a side view.Only the center electrode 420 has a fixation device such as needle 421.In FIG. 14a, the center fixation device is not an electrode. The entirearray is contained within a flexible polyurethane (or other polymeri c)coating. Electrodes 423-426 rest on the tissue without active fixation.An array with no active fixation is shown in two views in FIG. 13.Electrodes 410-413 encircle the tumor and wire bundle 414 connects tothe generator.

[0116]FIG. 15 is similar to FIG. 13 except that it has a fixation hook430 to hold the array in place.

[0117] Some practitioners may wish to avoid puncturing the tumor or itsimmediate periphery. FIG. 16 shows an array in top and side views that,by virtue of opening 440 is flexible and can be fixed around tumors ofvarious shapes and sizes. The number of electrodes and the fixationmechanism are not limited to those shown in FIGS. 12-16. Furthermore,such arrays may also include sensors as well as electrodes.

[0118] With reference to FIG. 17, an electrical generator 500 having alead 502 with an array of electrodes 506 on or around a tumor 504 isdepicted. The lead 502 and electrode array 506 will most likely betunneled subcutaneously and an array 506 such as that illustrated inFIG. 17 might present a problem to tunnel because of its size and shape.This may be solved by using a connector either at point A or point B sothat at least one end of the lead is free to tunnel. The connectorpermits the tunneling of only the narrow lead 502 itself Many of thelead connectors devised for and used in cardiac pacing would be suitablefor this application.

[0119] After the generator and leads are implanted, an electricaltherapy is desired by the physician that has not been built into thedevice. As illustrated in FIG. 18, a port 512 is built into thegenerator 500 that allows electrical input from outside the body to beconnected directly to the leads 502 bypassing the drive circuits 510 ofgenerator 500. This idea is similar to the port concept used in druginfusion implants (side ports in the Infusaid devices) in which drugscan be injected directly into the infusion catheter. In FIG. 19 a port526 is shown implanted under the skin 522. The port 526 is a palpableprotrusion on the implanted generator. A needle 520 inserted through theskin 522 into a self-sealing silicone diaphragm 524 would provideelectrical contact between an external generator and the tumor 504electrodes 528. Drug infusion devices using a Huber point needle willslice through the septum cleanly. FIG. 20 shows this in greater detail.In one embodiment the insulated needle 520 inserted into diaphragm 524as far as needle stop 530 has two electrodes 528 that touch electricalcontacts (shaded ovals) which are electrically connected to theelectrodes 528. Needle contact is checked electrically by the device bymeasuring the impedance between the electrodes or of a resistortemporarily placed across the output. Body fluid intrusion is preventedin this design. This invention makes it possible to leave out theelectroporation capability with its high voltage generation circuitryand power supply and provide the pulses in the clinic via the needleport. Electroporation might only be used infrequently in conjunctionwith chemotherapy and this would represent a cost saving as well as areduction in implant size and complexity.

[0120] Drug Infusion and ECT/Electrochemotherapy

[0121] A general benefit of combined ECT/electrochemotherapy and druginfusion is that, in the practice of implantable drug infusion pumps,reservoir and flow limitations dictate that chemotherapy drugs be highlyconcentrated. ECT/electrochemotherapy can increase the effectiveness ofthe drugs, thus permitting lower concentrations or less frequentreservoir refilling.

[0122] A combination ECT/electrochemotherapy and drug infusion devicehas already been mentioned above. It can, however, take several forms. Agenerator/infusion device 501 is shown in FIG. 21. The infusion catheter540 with electrodes 528 can be inserted directly into the tumor 504 orjust outside the tumor as shown in FIG. 21. Alternatively, the catheter540 can be positioned to infuse drugs to remote locations as in FIG. 22.Among those locations are veins and arteries 550. Hepatic arteryinfusion is often used for liver malignancies and venous infusion formany other cancers. Morphine is delivered intrathecally. Subdural andintra-peritoneal infusion is also used. To the best of the inventor'sknowledge insertion of the catheter tip directly at the tumor site hasnot been used. No literature has been found showing this approach.However, targeted administration is discussed in the literature assuperior to systemic.

[0123] A drug infusion device may be implanted that is physicallyseparated from the ECT/electrochemotherapy generator. This is shown inFIG. 23. Generator 501 electrically treats tumor 504 via electrodes 528.A separate infusion device 554 infuses drugs into a target site (vein,artery, or tumor) 550 via catheter 540. The generator 501 can controlthe pump 554 or vice versa. For example, the generator 501 could startand stop the pump 554 or the pump 554 could start or stop the generator501 in order to synchronize chemotherapy with electrical therapy.Synchronization could be programmed into each device pair 500, 554whereby each would perform a function at a given time. The generator 501could sense the pump 554 activity by monitoring, for example, a fluidsensor in the lead tip near electrodes 528 (if the pump catheter tip isat the tumor), the sound of the pump 554 (peristaltic rollers orsolenoid action) or a physiological effect of the drug. Conversely, thepump 554 may be designed to sense the generator 501. A program code isthen sent from one device to the other via the body bus 552.Alternatively a hardwired electrical connection is made at the tumorsite 504.

[0124] Passive synchronization is also possible. Assuming that no directcommunication has been built into the devices, how could the generator501 be designed so that its output precedes that of the pump 554? If thepump 554 is cyclic at regular intervals, the generator 501 can measurethe first interval and then start its output prior to the start of thenext interval. Another option is shown in FIG. 24. Assuming that thegenerator 564 and pump 566 have external patient controllers 560, 562for controlling the implanted devices 564, 566 noninvasively through theskin 522 or programmers (as many pumps do), the patient controllers 560,562 can be designed to communicate with one another and thus controlsynchronization of the two implants 564, 566. In one embodiment thecontrollers 560, 562 can be combined into one unit.

[0125] Variation of drug administration according to circadian rhythmsis often practiced. This maximizes dosage with minimal toxicity. Byvarying the electrical treatment according to the same rhythm theeffectiveness of the drug can be enhanced. Of course synchronization canalso be applied in continuous or bolus mode as well. Animal studies haveshown that, for commonly used cancer chemotherapeutic drugs, bothefficacy and toxicity to the host are related to the time ofadministration. These studies demonstrated that at levels capable ofkilling tumor cells, the chemotherapeutic agents can also kill orseverely injure normal tissues. However, the susceptibility of normaltissues to these powerful drugs varies rhythmically depending on thecircadian cycle, while tumor cells display a different time-relatedresponse. Thus, the timing of drug delivery becomes important forachieving therapeutic specificity. Many specialists currently believethat the amount of drug administered as well as adherence to monthlytreatment schedules are important to the ultimate success ofchemotherapy. (see Ranade reference)

[0126] Another embodiment of the present invention involves having morethan one drug reservoir. The drugs can be infused on separate schedulesand the patient can be permitted to control one drug but not the other.For example, the pain killer morphine (delivered intraspinally) can becontrolled by the patient.

[0127] Several sensor applications at the tumor site have been disclosedabove. Another can be added—sensing the drug administration. Forexample, if the drug is charged, as they often are, the sensed charge isproportional to the amount of drug effectively reaching the tumor. Thiscan be used for closed-loop control.

[0128] Several designs for catheters used to infuse drugs at the tumorsite are drawn in FIG. 25. A drug infusing catheter whose tip 570 is atthe tumor site may be designed with fixation means, one of which 572 isillustrated in FIG. 25a. The catheter may include an electrode forECT/electrochemotherapy. The electrode 574 may be designed as shown inFIG. 25b connected electrically via internal conductor 576.Alternatively, the electrode 574 conductor 578 may be external to thecatheter as in FIG. 25c. Little mechanical stress is expected on thecatheter or conductors post-implant.

[0129] An electrode array 580 may be designed into the catheter as shownin FIG. 25d. Again, the conductors may be external to the catheter tube.Any number of electrodes may be included. A novel catheter design isillustrated in FIG. 25e. The catheter is equipped with multipleapertures 582 for access to different parts of the tumor. The branchesor their apertures 580 may be designed to provide the same amount ofdrug at each site. Another catheter with multiple apertures 582 is shownin FIG. 25f Each of these designs can also include electrodes forelectrical treatment.

[0130] Yet another catheter design is based upon the use of a porousdrug-absorbing material 584 laid over the tumor 504 to help spread thedrug from the catheter 540 as shown in FIG. 26a. In FIG. 26b the tumoris not shown in order to better illustrate the addition to the porousmaterial 584 of concentric electrodes 528 for electrical treatment.Another electrode configuration is shown in FIG. 26c in which multiplepoint electrodes 528 are configured on porous material 584.

[0131] An electrode array may be used to steer or spread charged drugsprovided by a catheter at the tumor site. In FIG. 27 a negativelycharged drug 588 flows from a catheter 586 towards the center of athree-electrode array 506. The positively charged electrode 506 issequenced to direct the drug 588. In FIG. 28a the drug flow is initiallydirected at the center of the tumor 590. After a period of time thetumor 591 shrinks and the drug is redirected towards the new tumor siteas shown in FIG. 28b. Sensing of tumor volume changes are included as adevice feature in the invention. Also, the presence of the drug changesthe tumor impedance and thus the electrical load on the generator. Thesesensed parameters are used in locating the optimum locations for drugsteering. The invention of electrode drug steering can also be appliedto drug infusion for noncancer applications.

[0132] If ECT/electrochemotherapy is used with drugs injected directlyinto the tumor via a hypodermic needle, the tips of the electrical leador array can be made radio-opaque to help avoid accidentally contactingand puncturing the lead.

[0133] The drugs most often mentioned in the ECT/electrochemotherapyliterature are Adriamycin and Bleomycin. Fortunately they are bothsuitable for implantable infusion pumps. This means of delivery isadvantageous for Adriamycin because its cardiotoxicity is scheduledependent.

[0134]FIG. 29 illustrates the principle of an electrophoretic drug pump.It is explained in U.S. Pat. No. 4,639,244 granted to Rizk in 1987entitled Implantable electrophoretic pump for ionic drugs and associatedmethods. The ionic drug is contained in a reservoir 600 and diffuses 604through a membrane 606 which may be made of cellulose. The diffusionrate is controlled by two porous electrodes 602 placed on each side ofthe membrane and provided with direct current or pulsed direct current.The natural diffusion can be either enhanced or retarded by the level ofcurrent provided. The porous electrodes may be made of carbon mesh orplatinum mesh, for example.

[0135] This may be applied to the implantable Electrochemical Therapy orElectrochemotherapy device as shown in FIG. 30. FIG. 30 is a crosssection of the catheter having a central lumen 616 through which anionic chemotherapy drug can flow 604. Disposed on each side of thecatheter are two electrodes 612 used for supplying the current for ECTor Electrochemotherapy. They are electrically connected to the implantedgenerator by the conductors 614 shown in the figure. A porous membrane606 is shown at the end of the lumen 616 and a porous extension 610 ofeach electrode 612 is disposed on each side of the membrane 606. Thusthe electrodes 612 control flow of the chemotherapy drug whilesimultaneously providing ECT or Electrochemotherapy to the tumor. Ifmicroampere current levels are provided, very little drug will flow.However, milliampere or greater levels of current can be applied tosupply a greater flow of drugs or a bolus of drugs.

[0136] The same principle can be applied to other electrodeconfigurations such as those in FIG. 25. In those cases the solidelectrodes would be external to the body of the catheter.

[0137]FIG. 31 shows a three-dimensional view of the end of a catheter inwhich the electrodes 624 are arranged as bands around the circumferenceof the catheter. Either the electrode at the distal end alone or bothelectrodes may be inserted within the tumor. FIG. 31 also shows thelocation of polymer material 622, a porous extension of the electrodeover the membrane 620 and the flow of the drug 604. A side view of thiscatheter end is depicted in FIG. 32. Each of the two conductors 636 isconnected to its respective electrode 634 and 642 typically by a weld asrepresented by the gray ovals 632. The conductors are continued distallyto the respective porous extension 640 on either side of the porousmembrane 630. FIG. 32 also depicts the lumen 638, the drug flow 604, andthe location of the polymer regions 644.

[0138] Methods for Eliminating Possible Corrosion of Electrodes inElectrochemical Therapy and Electrochemotherapy

[0139] Clinicians and researchers have shown that anodes and cathodesmay often be interchanged without adverse consequences when usingelectrochemical therapy and electrochemotherapy. Some possibleexceptions are for continuous oxygen production or electrophoresis. Insituations in which the current or voltage and/or the duration oftherapy (coulombs delivered) are large, and in combination with certainsusceptible electrode materials, there may be electrochemicaldegradation of the electrodes (corrosion) occurring over a period oftime. This invention contemplates remedying this problem by periodicreversals in polarity of the D.C. applied in electrochemical therapy andby periodic reversals in polarity of the pulses applied inelectrochemotherapy.

[0140] In electrochemical therapy, for example, as shown in FIG. 33, inone embodiment the generator is designed so that, after a long period ofpositive polarity 700 represented by time interval t₁, the polarityautomatically reverses for another period 701 represented by t₂ and,after another long period of time t₃ reverses again, etc. In practiceall intervals t_(i) may be equal and typically may be on the order ofhours or weeks in length. For higher amplitude stimulation or formaterials more susceptible to corrosion the intervals may be on theorder of minutes.

[0141] In electrochemotherapy the method is illustrated in FIG. 34 wherethe comments above concerning t_(i) also apply. Positive polarity pulsesequences 704 are switched to negative polarity pulse sequences 706 atthe end of time interval t₁. These continue for the duration of t₂.

[0142] As a further means to prevent the effects of corrosion, the useof redundant electrodes is proposed. With reference to FIG. 35,electrodes 712 and 714 are shown inserted into tumor 710. Electrode 712may be used in the circuit for a period of time (typically months) andthen electrode 714 is used in the place of electrode 712 for a secondperiod of time, etc. Switch 716 is used to switch between the twoelectrodes. In point of fact, any number of electrodes may be employedin such a scheme. In one embodiment, sensing the effects of corrosionmay automatically cause switching from one corroding electrode to thenext uncorroded electrode. The electrodes may be located on separateleads or may be on the same lead.

[0143] If the electrodes are contained on the same lead as shown in FIG.36, they may be implemented by means of a segmented electrode assembly.In FIG. 36, lead 724 is inserted in tumor 710 and has two electrodesegments 720 and 722. It should be noted that the illustrated placementof the electrodes within the tumor is shown for example only. Theelectrodes may be external to the tumor as well.

We claim:
 1. An implantable medical device for the treatment of cancerconsisting of: a battery and circuitry, where the battery and circuitryare both contained within a hermetically sealed device housing, and atleast one electrode where the battery is operably connected to thecircuitry, the circuitry is operably connected to the electrode, and thecircuitry is capable of delivering direct current electrical therapy forover about 1 minute essentially continuously to at least one electrodethereby reducing the size of solid cancer tumors.
 2. The device of claim1 in which the electrical therapy involves the use of multiple voltages.3. The device of claim 1 in which the electrical therapy which thedevice is capable of delivering involves the application of voltagesbetween 1 volt and 20 volts.
 4. The device of claim 1 in which theelectrical therapy which the device is capable of delivering involvesthe application of voltages for a time period of between 1 minute and 1day.
 5. The device of claim 1 in which the electrical therapy which thedevice is capable of delivering involves voltages and time periodssufficient for changing the pH by at least 2.0 inside a tumor.
 6. Thedevice of claim 1 in which the electrical therapy which the device iscapable of delivering involves the application of voltages of between 20mV and 500 mV.
 7. The device of claim 1 in which the electrical therapywhich the device is capable of delivering involves the application ofvoltages for a time period of between 1 hour and 1 week.
 8. The deviceof claim 1 in which the electrical therapy which the device is capableof delivering involves voltages and time periods useful for attractingwhite blood cells.
 9. The device of claim 1 in which the electricaltherapy which the device is capable of delivering involves theapplication of voltages of between 100 mV and 10 V.
 10. The device ofclaim 1 in which the electrical therapy which the device is capable ofdelivering involves the application of voltages for a time period ofbetween 1 to 120 minutes.
 11. The device of claim 1 in which theelectrical therapy which the device is capable of delivering is poweredby an external power source rather than by said battery.
 12. The deviceof claim 1 in which the electrical therapy which the device is capableof delivering also involves the application of voltage pulses of between20 and 900 volts.
 13. The device of claim 1 in which the electricaltherapy which the device is capable of delivering also involves theapplication of voltage pulses with a pulse width of between 100 μs and20 ms.
 14. The device of claim 1 in which the electrical therapy whichthe device is capable of delivering also involves the application ofvoltage pulses with a spacing period of between 100 μs and 1 second. 15.The device of claim 12 in which the electrical therapy which the deviceis capable of delivering involves the application of between 1 and10,000 voltage pulses.
 16. The device of claim 1 in which the electricaltherapy which the device is capable of delivering also involves voltagesand pulse widths useful for forcing open tumor cell membranes to betterallow the flow of therapeutic substances.
 17. The device of claim 1 inwhich the device is capable of monitoring at least one voltage fromwithin tissue.
 18. The device of claim 17 in which the electricaltherapy which the device is capable of delivering is adjusted accordingto the sensed tissue voltage.
 19. The device of claim 18 in which theelectrical therapy which the device is capable of delivering involvesvoltages in the range of 20 mV to 500 mV.
 20. The device of claim 18 inwhich the electrical therapy which the device is capable of deliveringinvolves time durations in the range of 1 hour to 1 month.
 21. Thedevice of claim 1 in which the electrical therapy which the device iscapable of delivering to the at least one electrode involves bothpositive and negative voltages.
 22. The device of claim 1 in which anelectrical port contact is added to the side in order to receiveexternally generated electrical therapies.
 23. The device of claim 1with the additional element of a drug reservoir.
 24. The device of claim1 with the additional element of a drug pump.
 25. The device of claim 1with the additional element of a communication means to synchronizetherapy with a drug delivery system.
 26. The device of claim 1 with theadditional element of circuitry to alternate output polarities to reducethe levels of electrode corrosion and degradation.
 27. A method oftreating solid tumor cancers comprising the steps of: (1) implanting atleast one catheter into or near a tumor, (2) implanting a source ofchemotherapeutic drug, (3) connecting the catheter to the source ofchemotherapeutic drug, and (4) delivering the chemotherapeutic drug intothe tumor from the source of chemotherapeutic drug.
 28. The method ofclaim 27 with the additional step of delivering a therapeutic electricalcurrent.
 29. The method of claim 27 with the additional step ofsynchronizing a therapeutic electrical current delivery.
 30. The methodof claim 27 with the additional step of synchronizing the delivering ofthe chemotherapeutic drug to a therapeutic electrical current delivery.31. The method of claim 27 with the additional step of synchronizing thedelivering of the chemotherapeutic drug to the circadian rhythm.
 32. Themethod of claim 27 in which the step of delivering of thechemotherapeutic drug is performed through the use of a catheter with afixation means.
 33. The method of claim 27 in which the step ofdelivering of the chemotherapeutic drug is performed through the use ofa catheter which also delivers electrical therapy.
 34. A method oftreating solid tumor cancers comprising the steps of: (1) implanting atleast one electrode into or near a tumor, (2) implanting a source ofelectrical power, (3) connecting the electrode to the source ofelectrical power and (4) delivering electrical current into the tumorwith alternating polarities in order to deliver the electrical therapyto the tumor without causing extensive corrosion of the electrodes.